17alpha-unsaturated-halohydrocarbon-17beta-hydroxy-19-nor-4, 9-androstadiene-3-one 17-ethers



United States Patent I 3,337,537 170: UNSATURATED HALOHYDROCARBON- 17 8HYDROXY 19 NOR 4,9 ANDROSTA- DIENE-3-0NE 17-ETHERS John Fried, PaloAlto, Calif., and Thomas F. Bry, Linden, N.J., assignors to Merck & Co.,Inc., Rahway, N.J., a corporation of New Jersey N0 Drawing. Filed Oct.18, 1965, Ser. No. 497,479 23 Claims. (Cl. 260-2395) This invention isconcerned generally with novel steroid compounds and processes forpreparing same. More particularly it relates to novell7a-halohydrocarbon-19-nor- 4,9-androstadiene-3-one, and to closelyrelated compounds, in particular the 17 3 ethers thereof such as the17fi-alkyl, 17B-cycloalkyl, 17/3-aralkyl ethers, 17p unsaturatedhydrocarbon ethers and 17/3 substituted amino alkyl ethers, and the17,6-alky1 carbonates.

The compounds prepared by our invention are valuable as orally andparenterally active progestational agents, which also have the propertyof inhibiting gonadotropin secretion. The compounds are useful in thetreatment of various human ailments requiring progestational form oftherapy as Well as the synchronization of the estrus in domesticanimals. 1

This is a continuation-in-part of Ser. No. 234,204, filed Oct. 30, 1962,which is a continuation-in-part of Ser. No. 128,977, filed Aug. 3, 1961,now United States Patent No. 3,096,353 which is a continuation-in-partof Ser. No. 99,- 668, filed Mar. 31, 1961, which, in turn, is acontinuationin-part of Ser. No. 88,575, filed Mar. 2, 1961, now UnitedStates Patent No. 3,072,646.

The presently invented compounds include compounds having the followingstructural formula:

. TV O wherein R is a hydrocarbon radical having from 1 to 8 carbonatoms, for example, an alkyl radical suitably ethyl, methyl, butyl, amylor hexyl, a cycloalkyl radical such as cyolopentyl or cyclohexyl, or anaralkyl radical such as benzyl, or an unsaturated aliphatic radical, asubstituted amino alkyl radical, an alkoxy carbonyl radical, or thelike, and Y is an unsaturated halogenated hydrocarbon radical containingfrom 2 to 3 carbon atoms such as trifiuorovinyl, trifluoromethylvinyland trifluoromethylethynyl.

The 17,8-ethers of these 4,9-androstadiene-3-ones are prepared, inaccordance with the presently invented process, starting with3-methoXy-19-nor-2,5(10)-androstadiene-17-one, which has the followingstructural formula:

OHsO l 3,337,537 Patented Aug. 22, 1967 mide, trifiuoromethylethynylmagnesium bromide, and the like to form the corresponding17oc-Sl1bSlltl1i6d-17B-11Y- droxy steroid, for example the17a-trifluorovinyl-17B-hydroXy-19-nor-2,5 (10)-androstadiene which hasthe following structural formula:

the 17st substituted-3-methoxy-19-nor-2,5 (10)-androstadiene-17B-ol isconverted into the corresponding 17/3-substituted-17fl-hydroxy 19 nor 5(10) androstene-3-one which has the following formula:

wherein Y is selected from the group consisting of trifluorovinyl,trifluoromethylvinyl, and trifluoromethylethynyl by reaction with a weakorganic acid such as acetic acid. For example, a mixture of the steroidand glacial acetic acid in an aqueous solution of absolute ethanol anddioxane is left standing at room temperature for several hours.

The 170a substituted-17B-hydroXy-19-nor-4,9-androstadiene-B-one whichhas the following formula:

wherein Y is as above may be prepared by treatment of the17a-substituted-17,8-hydroxy-19-nor-5 (10)-androstene- 3-one withapproximately one equivalent of bromine in pyridine solution, or withpyridine perbromide hydrobromide.

The 17st substituted-l7fi-hydroxy-19'-nor-4,9androstadiene-3-ones ofthis invention are readily converted into the corresponding17,8-arylalkyl, l7fi-alkyl ethers, 17,8- cycloalkyl ethers,17B-unsaturated aliphatic ethers and Uri-substituted amino alkyl ethersby reaction when an aralkyl, an alkyl, a cycloalkyl, or unsaturatedaliphatic or a substituted amino alkyl halide or sulfate and a base.

In one modification of this process the 17fl-hydroxy compound as reactedwith an halide and silver oxide in a solvent such as dialkylalkanolylamide such as dimethyl formamide and the like to form thecorresponding 17/3- ether. The alkyl halideswhich may be used for thispurpose include methyl iodide, ethyl iodide, and propyl iodide,

alkyl halides such as diethyl amino ethyl bromide, pyrrolidyl ethylbromide and morpholino propyl bromide also may be used.

The steroid alcohol, for example l7ot-trifluorovinyl-l7{3-hydroxy-l9-nor-4,9 androstadiene 3 one is mixed with solvent, forexample dimethyl formamide in the presence of the alkyl halide such asethyl iodide, and silver oxide is added. The mixture is stirred at fromabout 10 to about 80 C. for from 20 to 6 days, from 15 C.30 C. for 4days being preferred, a small amount of silver oxide being added eachday. The product is then isolated. In one mode of isolation a reactioninert, Water immiscible solvent, for example a halogenated hydrocarbonsolvent suitably chloroform is added to the reaction mixture which isthen stirred and filtered. The solvent is removed from the filtratepreferably by evaporation under reduced pressure and the residuechromatographed.

Alternatively the 17/3-hydroxy steroid may be taken up in a reactioninert organic solvent, such as aromatic hydrocarbon solvent, forexample, benzene or toluene, and treated with an aliphatic halide, anyof the aralkyl, alkyl, cycloalkyl, unsaturated aliphatic and substitutedamino alkyl halides listed in the above-mentioned modification of theprocess being suitable, in the presence of an alkali metal hydride suchas sodium or potassium hydride to produce the 17,8-ether.

The steroid alcohol, for examplel7u-trifluoro-methylvinyl-l7fi-hydroxy-19-nor-4,9-androstadiene-3-one isdissolved in reaction inert organic solvent, for example, benzene andthe aliphatic halide in a similar solvent, for example cyclopentyliodide in benzene is added. A small excess of halide is used, an excessof from to about being preferred. The alkali metal hydride, suitablysodium hydride is then suspended in the same solvent and added to themixture. The mixture is then agitated for from about 1 to about 36 hoursat a temperature of from 10 to 80 C., agitation for 18 hours at fromabout C. to about C. being preferred. The product is then isolated. Inone suitable method of isolation, water is added to the mixture todestroy any remaining alkali metal hydride and the mixture extractedwith a reaction inert Water immiscible solvent such as benzene or ether.The organic extract is then dried over a suitable drying agent, such aspotassium carbonate and filtered. The solvent is then removed, suitablyby evaporation under reduced pressure and the residue further purifiedby chromatography.

In yet another modification of the process, the 17,8- hydroxy steroid isreacted with an aryl or alkyl alkali metal salt such as methyl lithium,butyl lithium or phenyl lithium-to produce a corresponding 17/3-oxylithium salt which is then treated with an alkyl or cycloalkyl halide.Any of the halides utilized in the previous modification of this processbeing suitable to produce the desired 17;?- aralkoxy, l7B-alkoxy or17fi-cycloalkoxy steroid.

The steriod alcohol, for example17a-trifluoro-methylethynyl-l7/3-hydroxy 19 nor-4,9-androstadiene-3-oneis taken up in an ether, diethyl ether or tetrahydrofuran beingpreferred. A solution of an aryl or alkyl alkali metal salt suitablyphenyl lithium or buty lithium in ether or tetrahydrofuran is thenadded. The mixture is then agitated 'for from about 1 to about '4 hoursat from about 10 to about 30 C. in an inert atmosphere, a nitrogenatmosphere being preferred. A solution of the aralkyl, alkyl orcycloalkyl halide in a similar solvent, for example ether ortetrahydrofuran is then added and the mixture agitated at from about 10C. to about 80 C. for a further period of from about 10 to about 24hours, agitation at about 15 C.30 C. for about 18 hours being especiallypreferred. The product is then isolated, suitably a saturated brinesolution is added to the mixture and the mixture extracted with a waterimmiscible solvent such as benzene or ether. The organic extract is thendried over a suitable drying agent such as sodium sulfate, filtered andthe solvent removed, preferably by evaporation under reduced pressure.The residue is then further purified by chromatography.

In another modification of the process the 17fi-hydroxy steriod, forexample17a-trifluoromethylethynyl-l7fi-hydroxy-19-nor-4,9-androstadiene-3-oneis treated with a dialkyl sulfate in an aqueous alkaline medium toproduce the corresponding 17,8-alkoxy compounds. The diaralkyl, dialkyland dicycloalkyl sulfates which may be used in this modificationincludes dimet-hyl sulfate, diethyl sulfate, dipropyl sulfate,diisopropyl sulfate, dibutyl sulfate, diisobutyl sulfate, diamylsulfate, diisoamyl sulfate, dihexyl sulfate, dibenzyl sulfate and thelike. Also suitable are the cycloalkyl sulfates such as dicyclopentylsulfate, dicyclohexyl sulfate, and the like. Sodium or potassiumhydroxide in aqueous solution are preferred as the alkaline medium.

The steroid alcohol for example,l7a-trifiuoro-methylethynyl-l7/3-hydroxy 19 nor-4,9-androstadiene-3-oneis taken up in a reaction inert solvent such as benzene toluene, etheror tetrahydrofuran and added to a mixture of the dialkyl sulfate in theaqueous alakaline medium. It is preferred to use a small excess of thedialkyl sulfate, in excess of about 5% to about 20% being suitable. Themixture is then allowed to stand for from 1 to 24 hours at a temperatureof from about 10 to about C., however, it is preferred to let themixture stand for about 18 hours at from about 15 C. to about 30 C.Where the solvent utilized is substantially immiscible with the aqueousmedium it is preferred to agitate the mixture during the reaction time.The product is then isolated. In one method of isolation the mixture isextracted with a reaction inert water immiscible solvent such as benzeneor toluene. The extract is then dried over a drying agent for exampleover potassium carbonate, filtered and the solvent removed, suitably byevaporation under reduced pressure. The residue is then further purifiedby chromatography.

The presently invented compounds include the followmg:17a-trifluorovinyl-19-nor-4,9-androstadiene-3-one-175- methyl ether,17/3-trifluoromethylvinyl-l9-nor-4,9-androstadiene-3- one-l7,8-ethylet-her, 17ot-trifiuoromethylethynyl-l9-nor-4,9-androstadiene-3-one-17 3-propyl ether,17a-trifluorovinyl-19-nor-4,9-androstadiene-3-one-17,8-

butyl ether, l7u-trifluoromethylvinyl-l9-nor-4,9-androstadiene-3-one-17,6 isobutyl ether,l7a-trifluoromethylethynyl-l9-nor-4,9-androstadiene- 3-one-17 8-amylether, 17a-trifluorovinyl-19-nor-4,9-androstadiene-3-one-17B- hexylether, l7a-fluoromethylvinyl-l9-nor 4,9-androstadiene-3-one-17,8-cyclopentyl ether,17a-trifluoromethyletl1ynyl-19-nor-4,9-androstadiene-3-one-17p-cyclohexyl ether,17a-trifiuoromethylvinyl-l9-nor-4,9-androstadiene-3- one-17,8-benzylether and 17ot-trifluoromethylethynyl-l9-nor-4,9-androstadiene-3-one-17B-benzyl ether,17a-trifiuorovinyl-l9-nor-4,9-androstadiene-3-one-17/8- allyl ether,17tx-trifluoromethylvinyl-19-nor-4,9-androstadiene-3-one-l7fi-cyclohexenyl ether,17a-trifluoromethylethynyl-l9-nor-4,9-androstadiene-3-one-l7,B-diethylamino ethyl ether,

17 a-trifluoromethylvinyl- 1 9-nor-4,9-androstadiene-3-one-l7a-pyrrolidyl ethyl ether andehtyl-17u-trifluormethylethynyl-l9-nor-4,9-androstadiene-3-one-l7fldiethylaminoethyl ether,

17a-trifluoromethylvinyl-19-nor-4,9-androstadiene-3- one-l7fi-pyrrolidylethyl ether and 17a-trifiuoromethylethynyl-l9-nor-4,9-androstadiene-3-one-17,8-rnorpholino propyl ether.

The compounds of this invention may be administered alone or associatedwith a pharmaceutical carrier, choice of which depends upon theproperties of the active compound and standard pharmaceutical practice.Generally the compound is administered in dosages of the same order ofmagnitude as other progestational agents such as norethisterone anddosage units may take the form of tablets, powders, capsules, elixirs,or syrups which are particularly useful for oral ingestion. Liquiddiluents are employed as a condition for parenteral use. Thefoll-owingexamples are given by way of illustration only and are not intended as alimitation of this invention, many apparent variations of which arepossible without departing from the intent and scope thereof.

Example 1 A 500 cc. three-neck round bottom flask is fitted with a DryIce condenser, a dropping funnel and a magnetic stirrer. After theaddition of 4.0 g. of magnesium, the

entire system is swept with nitrogen and flame dried. One hundred cc. ofdry tetrahydrofuran is added to the magnesium and 13 g. oftrifluorovinyl bromide is bubbled into the solution held at 25 C. withstirring. The solution is decanted into a dry flask and stored. Asolution of 500 mg. of 3-methoxy-2,5(l0)-androstadiene-17-one which isdried by azeotropic distillation from benzene, is added in 5 cc. ofbenzene and 5 cc. of dryether to 50 cc. of the trifluorovinyl magnesiumbromide solution prepared above. The reaction is stirred for 16 hours atroom temperature. Water is then added and the mixture extracted withether. The organic extracts are Washed with fluoromethylethynyl 3methoxy-l9-nor-2,5(10)-andro stadiene- 1 7,8-01.

Example 2 To 410 mg. of 17a-trifluorovinyl-3-methoxy-19-nor-2,5(1O)-androstadiene-l7/3-ol in 4.1 cc. of tetrahydrofuran and 18.45cc. of absolute ethanol is added 8.2 cc. of

glacial acetic acid and 0.5 g. of sodium acetate in 4.1

cc. of Water. This reaction mixture is left stirring at room temperaturefor 5 hours. It is then poured into an icesodium bicarbonate solutionand extracted with benzene.

The benzene extract is washed with water until the Washings are justslightly basic, dried over sodium sulfate and concentrated in vacuo. Thecrude product is chromatographed on 40 g. of silica gel by charging witha mixture of 1 part benzene and 1 part petroleum ether, and eluting withmixtures of petroleum ether and ether to yield17a-trifluorovinyl-17,8-h'ydroxy-19-nor-5 10) androstene- I 3-one.

In accordance with the above procedure but starting with17a-trifluoromethy lvinyll9-no-r-3-methoxy-2,5 (10)-androstadiene-17B-ol and 17ot-trifluoromethylethynyl-3-methoxy-l9-nor-2,5(10)-androstadiene-l7,8-ol in place of17a-trifluorovinyl-3-methoxy-19-nor-2,5 10)-androstadiene-17fl-ol thereis obtained 17a-trifluoromethylvinyll7fl-hydroxy-19-nor-5 10)-androstene-3-one and 17a-trifluoromethylethynyl 17phydroxy-19-nor-5(10)-androstene-S-one.

Example 3 A mixture of 500 mg. of 17a-fluorovinyl-17B-hydroxy-19-nor-4,9-androstadiene-3 one of dimethyl formamide, 20 ml. of ethyliodide, and 1.5 grams of silver oxide are stirred at room temperaturefor 4 days, an additional /2 gram of silver oxide being added at the endof each day. ml. of chloroform is then added to the reaction mixture andthe mixture is stirred for one hour and filtered. The filtrate isevaporated to dryness and the residual oil is chromatographed over acidwashed alumina and eluted with mixtures of ether and petroleum ether togive 17rx-tn'fiuorovinyl-l9-nor-4,9-androstadiene 3 one- 17B-methylether.

In accordance with the above procedure starting With 17atrifluoromethylvinyl-17,8-hydroxy-l9-nor-4,9-androstadiene-3-one, inplace of 17m-trifiuorovinyl-17fi-hydroxy-l9-nor-4,9-androstadiene-3-onethere is obtained 17a-triflnoromethylvinyl-19 nor 4,9 androstadiene-3one-17fl-methyl ether and l7rx-trifluoromethylethynyl-19-nor-4,9-androstadiene-3-0ne-17,8-rnethyl ether.

In accordance Wtih the above procedure but starting With any of theabove-mentioned 17(3-hydroxy androstadienes and using ethyl, propyl,butyl, amyl, cyclopentyl, cyclohexyl allyl, cyclohexyl diethylaminoethyl, pyrrolidyl ethyl, morpholino ethyl, and benzyl iodide or bromidein place of methyl iodide, there are obtained the correspondingl7l3-ethoxy, l7B-propoxy, 17/3-butoxy, 17,8- amoxy, 17B-hexoxy,l7fl-cyclopentoxy, 17,8-oyclohexoxy, 17c allyloxy, cyclohexenoxy, 17,8diethylamino ethoxy, 17,6-pyrrolidyl ethoxy, 17,8-morpholino ethoxy,17,8-benzyloxy androstadienes.

Example 4 To a mixture of 710 milligrams of17a-trifluoromethylvinyl-17,8-hydroxy-19nor-androstadiene-3-one and 20ml. of cyclopentyl iodide in 100 milliliters of benzene and the mixturestirred at about 20 C. for 2 days under a nitrogen atmosphere. 100milliliters of water are then added to the mixture which is then stirredfor a further hour. The organic layer is separated and the water layerextracted wth benzene. The combined benzene extracts are then dried overanhydrous potassium carbonate, filtered, and evaporated under reducedpressure. The residue is then chromatographed over acid washed aluminaand eluted with mixtures of ether and petroleum ether to give 17atrifluoroethylvinyl-l9-nor-4,9-androstadiene-3-one- 18B-cyclopentylether.

In accordance with the above procedure starting with 17a-trifluorovinyl17,8 hydroxy 19 nor 4,9 androstadiene-B-one,17tx-trifluoromethylethynyl-17,8-hydroxy-19-nor-4,9-androstadiene-3-one, in place ofl7a-trifluoromethylvinyl-l75-hydroxy-19-nor 4,9 andnostadiene-3- onethere is obtained 17a-trifluorovinyl-19-nor-4,9-andr0-stadiene-3-one17,8-cyclopentyl ether and 17t-trifluoromethylethynyl-19-nor-4,9-androstadiene 3 one 17f!-cyclopentyl ether.

In accordance with the above procedure but starting with any of theabove-mentioned l7fi-hydroxy androstadienes and using methyl, ethyl,propyl, butyl, amyl, hexyl, cyclohexyl, and benzyl iodide or bromide inplace of cyclopentyl iodide, there are obtained the corresponding 17;?-methoxy, Uri-ethoxy, 17fl-propoxy, 17 8-but0xy, 17,8-amoxy, 17,8-hexoxy,l7fi-cyclohexoxy, 17,8-benzyloxy androstadienes.

Example 5 To a solution of 744 mg. of 17a-fluoroethylethynyl-17,8-hydroxy-19-nor-4,9-androstadiene-3-one in 30 ml. of tetrahydrofuran isadded a solution containing 29 m. of phenyl lithium. The mixture is thenstirred for 2 hours at 20 C. under nitrogen. A solution of 5 g. ofn-butyl iodide in 10 ml. of tetrahydrofuran is then added and themixture stirred under nitrogen at 20 C. for a further 18 hours. Thereaction mixture is then decomposed by the addition of a saturatedaqueous solution of sodium chloride. The mixture is then thoroughlyextracted with benzene and the organic extract dried over sodiumsulfate, filtered, and evaporated under reduced pressure. The residue isthen chromatographed over acid washed alumina and eluted with mixture ofether and petroleum ether to give l7a-trifluoromethylethynyl 19 nor 4,9androstadiene-3-one- 17an-butyl ether.

In accordance with the above procedure starting with 17 atrifiuoromethylvinyl-17fi-hydroxy-19-nor-4,9-androstadiene-3-one and17a-trifluorovinyl-17B-hydroxy-19-nor- 4,9-androstadiene-3-one, in placeof170t-IfifillOI'OIIl6thYlethynyl-17fl-hydroXy-l9-nor-4,9-andr0stadiene-3-0nethere is obtainedHot-trifiuoromethylvinyl-19-nor-4,9-androstadiene-3-one-17B-n-butylether and 17a-trifluor0vinyl-19- nor-4,9-androstadiene-3-one-17fln-butylether.

In accordance with the above procedure but starting with any of theabove-mentioned 17(3-hydroxy androstadienes and using methyl, ethyl,propyl, amyl, hexyl, cyclopentyl, cyclohexyl, and benzyl iodide orbromide in place of n-butyl iodide, there are obtained the corresponding175-methoxy, 17(3-ethoxy, 17fi-propoxy, 17fl-am0Xy, 17B- hexoxy,17/3-cyclopentyloxy, 17,8-cyclohexoxy, 17fl-benzyloxy androstadienes.

Example 6 To a mixture of 1 g. of dimethyl sulfate in 10 ml. of N-sodiumhydroxide is added a solution of 734 mg. of 17a trifluoroethyl 175hydroxy-l9-nor-4,9-androstadiene-3-one in 50 ml. of benzene. The mixtureis then vigorously agitated for 18 hours at 20 C. At the end of thistime the mixture may have formed an emulsion which is then reconstitutedinto its constituent parts by the addition of a small amount of ethanoland solid sodium chloride. The organic layer is then separated and theaqueous layer thoroughly extracted with benzene. The organic extract isthen dried over potassium carbonate, filtered and the solvent removed byevaporation under reduced pressure. The residue is then chromatographedover acid washed alumina and eluted with mixture of ether and petroleumether to give17a-trifiuorovinyl-19-nor-4,9-androstadiene-3-one-17B-methyl ether.

In accordance with the above procedure starting with 17mtrifiuoromethylvinyl 17B hydroxy 19-nor-4,9-androstadiene-3-one, and17a-trifluoromethylethynyl-17fi-hydroxy-l9-nor-4,9-androstadiene-3-one,in place of 17oc-trifluorovinyl17B-hydroxy-19-nor-4,9-androstadiene-3-one there is obtainedNor-trifiuoromethylvinyl-19-n0r-4,9-androstadiene-B-one-17/3-methylether.

In accordance with the above procedure but starting with any of theabove-mentioned 17fi-hydroxy androstadicues and using diethyl, dipropyl,dibutyl, diamyl, dihexyl, dicyclopentyl and dicyclohexyl sulfate thereare obtained the corresponding 17B-ethoxy, 17fl-propoxy, 17fi-butoxy,17B-amoxy, 17,8-hexoxy, 17fl-cyclopentyloxy androstadienes.

What is claimed is:

1. A compound selected from the group consisting of compounds having thestructural formula:

unsaturated halohydrocarbon radical selected from the group consistingof trifluorovinyl, trifiuoromethylvinyl and trifluoromethylethynylradicals.

2. 17a. substituted 17B-aralkoxy-19-nor-4,9-androstadiene-3-one whereinthe substituent at 17- is an unsaturated fluorohydrocarbon radicalhaving from 2 to 3 carbon atoms.

3. a substituted-17fi-cycloalkoxy-19-nor-4,9-androstadiene-3-one whereinthe substituent 17a is an unsaturated fluorohydrocarbon radical havingfrom 2 to 3 carbon atoms.

4. 17 a substituted I7B-alkoxy-19-nor-4,9-androstadiene-3-one whereinthe substituent at 17cc is an unsaturated fluorohydrocarbon radicalhaving from 2 to 3 carbon atoms.

5. l7-aliphatic ether of Not-substituted-Uri-hydroxy-19-nor-4,9-androstadiene-3-one wherein the substituent at 170a is anunsaturated fluorohydrocarbon radical having from 2 to 3 carbon atoms.

6. 17a-substituted-17,8-substituted aminoalkoxy-19-nor-4,9-androstadiene-3-one wherein the substituent at 170: is anunsaturated fluorohydrocarbon radical having from 2 to 3 carbon atoms.

7. 17a trifiuorovinyl-17/i-aralkoxy-19-nor-4,9-androstadiene-B-one.

8. 17a trifiuoromethylvinyl-17/3-alkoxy-19nor-4,9-andr0stadiene-3-one.

9. 170a trifiuoromethylethynyl-l7B-alkoxy-19-n0r-4,9-androstadiene-3-one.

10. 17a trifluorovinyl-17/3-methoxy-19-nor-4,9-androstadiene-3-one.

11. 17a trifiuoromethylvinyl-17B-methoxy-19-nor-4,9-androstadiene-3-one.

12. 17a trifluoromethylethynyl 17(3-methoxy-19-nor-4,9'-androstadiene-3-one.

13. 170a trifluorovinyl 17;? cyclopentoXy-19-nor-4,9-androstadiene3-one.

14. 17a trifiuoromethylethynyl 17fl-cyclopentoxy-19-nor-4,9-androstadiene-3-one.

15. 170: trifluorornethylethynyl-l7 8-cyclopentoxy-l9-nor-4,9-androstadiene-3-one.

16. 17a trifluoromethylethynyl-l7i3 benzyloxy-l9-nor-4,9-androstadiene-3-one.

17. 17a trifiuoromethylvinyl-17 8-benzyloxy-19-nor-4,9-androstadiene-3-one.

18. 170; trifiuoromethylvinyl-17B-allyloxy,19-nor-4,9-androstadiene-3-one.

19. 17a trifluoromethylethynyl-17B-allyloxy,19-nor-4,9-androstadiene-3-one.

20. 17a trifluorovinyl-17/3-allyloxy-19-nor-4,9-androstadiene-B-one.

21. 17a trifluorovinyl-17,6-pyrr0lidylethoxy-19-nor-4,9-androstadiene-3-one.

22. 17oz trifluoromethylethynyl-17B-pyrrolidylethoxy-19-nor-4,9-androstadiene-3-one.

23. 17a trifiuoromethylvinyl-17,3-pyrrolidylethoxy-19-nor-4,9-androstadiene-3-one.

References Cited Fried et al.: Journal of American Chemical Soc., volume83 (1961), pages 4 6634664 relied on. Copy in Scientific Library.

LEWIS GOTTS, Primary Examiner. ELBERT L. ROBERTS, Examiner,

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS HAVING THESTRUCTURAL FORMULA: